Molecular, cellular and clinical abnormalities in patients with xeroderma pigmentosum (XP) and with Cockayne's syndrome (CS) are being studied. We developed new assays using plasmids as tools to measure DNA repair and mutagenesis at the molecular level in cultured human cells. Despite different molecular abnormalities and clinical features, fibroblasts from a Japanese XP patient in complementation group A showed a similar plasmid UV hypermutability to that of a US XP-A patient and to that of a Japanese XP-F patient. Transformation of XP-A lymphocytes did not alter plasmid UV survival and mutagenesis but did change the spectrum of mutations, resulting in an increased proportion of G:C to A:T transitions. CS cells had defective repair of cyclobutane dimer type photoproducts but normal repair of non-dimer photoproducts. These abnormalities in repair of different photoproducts may be linked to the increased frequency of skin cancer in XP but normal cancer frequency in CS. Treatment of plasmid with the activated carcinogen, aflatoxin B1 epoxide (AFB1), showed decreased survival and increased mutations in the XP cells. Most mutations involved G's with the G:C to T:A transversion predominating. There was no correlation between the intensity of AFB1 binding and the frequency of mutations at individual G's. The long term study of chemoprevention of skin cancer in XP with 13-cis retinoic acid (Accutane) is continuing. We found high dose (2 mg/kg/da) oral 13-cis retinoic acid to be effective in preventing skin cancers but very toxic. A variable response to low dose (0.5 mg/kg/da) oral 13-cis retinoic acid was found in different patients ranging from almost complete tumor prevention to no beneficial effect. 13-cis retinoic acid was shown to reduce the frequency of chromosome breakage following in vitro exposure of lymphocytes to x-irradiation. The XP Registry demonstrated a median age of onset of skin cancers of less than 10 years and a more than 1000-fold increased frequency of skin and eye cancer in XP patients. The anatomic location of skin cancers indicates that although UV radiation exposure causes both melanoma and non-melanoma cancer, the mechanism of skin cancer induction is different for each type of cancer.